3-({4-[2-(4-Tert-butylphenyl)-1h-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]]pyrazi ne compounds

Abstract

The present invention relates to Gonadotropin Releasing Hormone (“GnRH”) (also known as Leutinizing Hormone Releasing Hormone) receptor antagonists.

1 . A compound which is the amorphous, ethanolate, or hydrate form of 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine.  
   
   
       2 . The compound of  claim 1 , wherein the compound is the amorphous form of 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine.  
   
   
       3 . The compound of  claim 1 , wherein the compound is the ethanolate form of 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine.  
   
   
       4 . The compound of  claim 3 , wherein the compound is 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine mono-ethanolate.  
   
   
       5 . The compound of  claim 3 , wherein the ethanolate is crystalline.  
   
   
       6 . The compound of  claim 5 , having an endotherm at about 141° C. on DSC at 10° C./min heating rate.  
   
   
       7 . The compound of  claim 5 , having an X-ray diffraction pattern having characteristic peaks expressed in degrees 20 at 9.701, 18.100, and 20.360.  
   
   
       8 . The compound of  claim 5 , having an X-ray diffraction pattern substantially the same as that shown in  FIG. 2B .  
   
   
       9 . The compound of  claim 1 , wherein the compound is a hydrate of 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine.  
   
   
       10 . The compound of  claim 9 , wherein the compound is a mono-hydrate.  
   
   
       11 . The compound of  claim 9 , wherein the compound is crystalline.  
   
   
       12 . The compound of  claim 11 , having an endotherm at about 141° C. on DSC at 10° C./min heating rate.  
   
   
       13 . The compound of  claim 11 , having an X-ray diffraction pattern having characteristic peaks expressed in degrees 20 at 7.449, 14.614, 16.442, and 18.780.  
   
   
       14 . The compound of  claim 11 , having an X-ray diffraction pattern substantially the same as that shown in  FIG. 3 .  
   
   
       15 . A method for modulating the activity of a Gonadotropin Releasing Hormone receptor, comprising contacting said receptor with an effective amount of a compound of  claim 1 .  
   
   
       16 . The method of  claim 15 , wherein the compound is a hydrate of 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine.  
   
   
       17 . The method of  claim 15 , further comprising determining the activity of said receptor.  
   
   
       18 . The method of  claim 17 , wherein said determination is made before said contacting step.  
   
   
       19 . The method of  claim 17 , wherein said determination is made after said contacting step.  
   
   
       20 . A method for treating a patient suspected of suffering from a condition associated with excessive Gonadotropin Releasing Hormone receptor activity, comprising administering to the patient a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       21 . The method of  claim 20 , wherein the compound is a hydrate of 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine.  
   
   
       22 . The method of  claim 20 , wherein said condition is prostate cancer, endometriosis, uterine fibroids, uterine cancer, breast cancer, ovarian cancer, testicular cancer, primary hirsutism, or LH surge.  
   
   
       23 . A pharmaceutical composition, comprising: 
 a compound according to  claim 1;  and    an additional active agent selected from the group consisting of at least one of androgens, estrogens, progesterones, antiestrogens, antiprogestogens, testosterone, antiprogestogens, angiotensin-converting enzyme inhibitor, angiotensin II-receptor antagonist, renin inhibitor, bisphosphonates, growth hormone secretagogues, 5a-reductase 2 inhibitor, a 5a-reductase 1 inhibitor, dual inhibitors of 5a-reductase 1 and 5a-reductase 2, antiandrogens, alpha-1 blockers, growth hormone, and luteinizing hormone releasing compounds.    
   
   
       24 . The composition of  claim 23 , wherein the compound is a hydrate of 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine.  
   
   
       25 . A method for converting amorphous 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine to a hydrate form, the method comprising: 
 dissolving amorphous 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]pyrazine in ethanol; obtaining the ethanolate form of 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl} methyl)pyrido[2,3-b]pyrazine;    contacting the ethanolate form with water at a temperature above 25° C.; and    crystallizing to obtain the hydrate form of 3-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl methyl)pyrido[2,3-b]pyrazine.    
   
   
       26 . The method of  claim 25 , wherein crystallizing includes filtering the solids to obtain the hydrate form and drying the solids at about about 40 to about 60° C. overnight.